Glutathione is an antioxidant substance that is widely distributed in the living body, and is a tripeptide that consists of cysteine, glutamic acid, and glycine. As the main reducing agent in the living body, glutathione plays an important role in cell protection by various types of oxidation-reduction metabolism, as well as in xenobiotic metabolism, repair processes, and the like by means of the SH groups that are the active sites of glutathione. As the substrate of glutathione peroxidase, glutathione detoxifies peroxides such as hydrogen peroxide and lipid peroxides that are generated in the living body. Furthermore, by being oxidized itself, glutathione also acts to protect the living body from oxidative damages (e.g., by the above-mentioned peroxides, free radicals, and the like).
In cases where the equilibrium between oxidation promoting substances and the mechanism of the antioxidation ability is such that the former substances take precedence, oxidative stress occurs. Furthermore, if the living body is subjected to excessive oxidative stress, xenobiotic and the like, the glutathione in the living body is consumed to the point of exhaustion, so that normal cell function cannot be maintained. Pathological conditions that are caused by a decrease in the intracellular concentration of glutathione include cell damage, inflammation, darkening, production of spots or freckles caused by exposure to ultraviolet radiation, acute or chronic alcoholic liver damage, liver disease, chronic renal insufficiency, pulmonary disorders caused by tobacco smoking or the like, idiopathic pulmonary fibrosis, cataracts, ischemic heart disease, Parkinson's disease, Alzheimer's disease, gastric ulcers, adult respiratory organ impairment syndrome, immune deficiency, marrow formation insufficiency, acquired immune deficiency syndrome, latent viral infections, aging phenomena and cancerous changes accompanying physiological aging, and the like.
Glutathione formulations have been used to treat the above-mentioned pathological conditions caused by a decrease in the intracellular concentration of glutathione. However, depending on the organ, the oral administration of glutathione may not have the expected effect. Treatment by means of injection promises a greater effect than treatment by oral administration. However, such treatment involves a number of problems: namely, the administration involves pain, a visit to the hospital or clinic is required, and the like. Since the quantity of glutathione in cells depends on the quantity of cysteine that is present in the cells, S-containing compounds that are used to increase this quantity of cysteine in cells have been disclosed in recent years (JP 01-26516 A, JP 02-45420 A, JP 05-301811 A, and JP 08-319242 A).
For example, such compounds include N-acetylcysteine, L-2-oxothiazolidine-2-carboxylic acid, glutathione esters, and the like. However, depending on the organ, even such compounds have not been satisfactory in terms of the effect obtained.
The quantity of expression and the activity of enzymes that condense glutamic acid and cysteine and enzymes that synthesize γ-glutamylcysteine are known as another factor that determines the quantity of glutathione in cells. The activity and amount of expression of such enzymes are regulated by various factors such as thermal shock, tumor necrosis factor (TNF-α) cytokines such as interleukin 1, hormones such as insulin and glucocorticoid, heavy metals, factors relating to cell proliferation and cell cycle, and the like. Furthermore, antioxidant response elements are present in the 5′ terminal regions of genes of these enzymes, so that the enzymes have a sequence that responds to antioxidant substances. The detailed mechanism is still not considered to be completely clear, but it has been reported that pulmonary edema induced by phosgene in mice can be prevented in advance by administering butylhydroxyanisole (which is used as an antioxidant in food products) and thus raising the glutathione concentration (Inhal. Toxical. 1999, 11 (9), pp. 855-871). However, it has not been reported that conventionally known antioxidants such as vitamin C, mannitol, amino acids (such as histidine) or antioxidants such as Olea europaea extracts (JP. 2000-128765 A, JP 2001-181632 A, and JP 2001-26518 A) and a hydrolysate of an Olea europaea extract (JP 09-78061 A) have a glutathione potentiating effect, and there is still no specific description of use in the prevention and treatment of the diseases cited above on the basis of such a mechanism of action.